The present invention relates to group A streptogramin derivatives of general formula: 
as well as their salts, which exhibit a particularly advantageous antibacterial activity.
Among the known streptogramins, pristinamycin (RP 7293), an antibacterial of natural origin produced by Streptomyces pristinaespiralis was first isolated in 1955. The pristinamycin marketed under the name Pyrostacine(copyright) consists mainly of pristinamycin IIA combined with pristinamycin IA.
Another antibacterial of the class of streptogramins: virginiamycin, has been prepared from Streptomyces virginiae, ATCC 13161 [Antibiotics and Chemotherapy, 5, 632 (1955)]. Virginiamycin (Staphylomycine(copyright)) consists mainly of factor M1 combined with factor S (VS).
Semisynthetic derivatives of streptogramins of structure: 
for which n is 0 to 2 have been described in patents EP 135410 and EP 191662. Combined with a semisynthetic component of group B streptogramins they manifest a synergistic action and can be used by the injection route.
In International Patent Application WO 99/05165, there have been described group A streptogramin derivatives of general formula: 
in which R1 is a radical xe2x80x94NRxe2x80x2Rxe2x80x3 or xe2x80x94NRxe2x80x2ORxe2x80x2xe2x80x3, R2 is hydrogen, methyl or ethyl, and he bond - - - is a single bond or a double bond, which are antimicrobial agents.
However, these derivatives do not achieve particularly high levels of activity and, moreover, do not always have a spectrum as broad as desired.
It has now been found that the group A streptogramin derivatives of general formula (I) in which:
R1 represents a halogen atom or an azido or thiocyanato radical,
R2 represents a hydrogen atom or a methyl or ethyl radical,
R3 represents a hydrogen atom, or the residue of an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclylaliphatic ester which may be substituted, and
the bond - - - represents a single bond (stereochemistry 27R) or a double bond,
and their salts when they exist, exhibit a particularly potent antibacterial activity, alone or combined with a group B streptogramin derivative, and/or also manifest a broadened spectrum compared with the usual spectrum for streptogramins.
According to the invention, when R1 represents a halogen atom, it may be chosen from fluorine, chlorine, bromine or iodine;
when the radical R3 represents the residue of an aliphatic, cycloaliphatic, aromatic, araliphatic, hydrocyclic or heterocyclylaliphatic ester which may be substituted, the latter may be chosen, by way of example, from Rxe2x80x23xe2x80x94COxe2x80x94 radicals for which Rxe2x80x23 is phenyl or phenylalkyl which are unsubstituted or which are substituted on the phenyl radical [with one or more radicals chosen from alkyl, optionally carrying a radical NRxe2x80x2Rxe2x80x3 in which the radicals Rxe2x80x2 and Rxe2x80x3, which are identical or different, may be hydrogen atoms or alkyl radicals which can form together with the nitrogen atom to which they are attached a 3- to 8-membered saturated or unsaturated heterocyclyl radical optionally comprising another heteroatom chosen from oxygen, sulfur or nitrogen, it being possible for the said heterocycle itself to be substituted with one or ore radicals (alkyl, hydroxyalkyl, alkyloxyalkyl, alkyloxycarbonylalkyl, aryl, heterocyclyl, heterocyclylalkyl, which are saturated or unsaturated and have 3 to 8 members, or xe2x80x94CH2xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3), or alternatively Rxe2x80x2 and/or Rxe2x80x3 may be a hydroxyalkyl radical, a phenyl radical, a 3- to 8-membered saturated or unsaturated heterocyclylalkyl radical, a radical xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3 for which NRxe2x80x2Rxe2x80x3 is as defined above, or alkyl or acyl radicals which are substituted with NRxe2x80x2Rxe2x80x3 which is as defined above], or alternatively Rxe2x80x23 may be chosen from phenyl or phenylalkyl radicals which are substituted on the phenyl radical with one or more radicals [chosen from alkyl, which may be substituted with an alkyloxy or alkylthio radical optionally carrying themselves a carboxyl radical or a radical NRxe2x80x2Rxe2x80x3 as defined above], or chosen from acyloxy which may be substituted with NRxe2x80x2Rxe2x80x3 as defined above), or alternatively Rxe2x80x23 may be chosen from alkyl or cycloalkyl radicals which are optionally substituted [with a carboxyl radical, a carboxyalkyldisulfanyl radical or with a radical NRxe2x80x2Rxe2x80x3, xe2x80x94CH2xe2x80x94NRxe2x80x2Rxe2x80x3, or xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3, or with an alkyloxycarbonyl, alkyloxy or alkyldi-sulfanyl radical which are optionally substituted with NRxe2x80x2Rxe2x80x3 or xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3 for which NRxe2x80x2Rxe2x80x3 is as defined above], or alternatively Rxe2x80x23 may be chosen from 3- to 8-membered saturated or unsaturated heterocyclyl radicals which are optionally substituted [with alkyl or acyl which are themselves optionally substituted with NRxe2x80x2Rxe2x80x3].
In general formula (I), unless otherwise stated, the alkyl or acyl radicals or portions are straight or branched and contain 1 to 12 carbon atoms, the heterocyclyl radicals may be chosen in particular from pyrrolidinyl, pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrizanyl, pyrimidinyl, pyridazinyl and imidazolidinyl, and the aryl radicals may be chosen in particular from optionally substituted phenyl and more particularly from phenyl which is substituted with alkyl, alkyloxy or halogen, or with a radical xe2x80x94CH2OH, xe2x80x94(CH2)nxe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94NHalkyl or xe2x80x94(CH2)nxe2x80x94N(alkyl)2.
The streptogramin derivatives of general formula (I) may be prepared by halogenating, converting to an azide or converting to a thiocyanate, a streptogramin derivative of general formula: 
in which R2 is as defined above, the bond - - - represents a single bond (stereochemistry 27R) or a double bond, and in which the hydroxyl function at the 14-position has been previously protected, followed by the removal of the protecting radical and where appropriate, in order to obtain a derivative of general formula (I) for which R3 is other than a hydrogen atom, introduction of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclylaliphatic ester residue which may be substituted (R3) according to the usual methods which do not alter the rest of the molecule.
The reactions for halogenating, converting to an azide or converting to a thiocyanate may be carried out in the presence of an aminosulfur trifluoride (for example diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor(copyright)), morpholinosulfur trifluoride) or alternatively in the presence of sulfur tetrafluoride, by means of a reagent such as a tetraalkylammonium, trialkylbenzylammonium or trialkylphenylammonium halide, azide or thiocyanate or by means of an alkali metal halide, azide or thiocyanate optionally supplemented with a crown ether. The fluorination reactions may also be carried out by the action of a fluorinating agent such as a sulfur fluoride [for example morpholinosulfur trifluoride, sulfur tetrafluoride (J. Org. Chem., 40, 3808 (1975)), diethylaminosulfur trifluoride (Tetrahedron, 44, 2875 (1988)), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor(copyright)). Alternatively, the fluorination reactions may also be carried out by means of a fluorinating agent such as hexafluoropropyldiethylamine (JP 2,039,546) or N-(2-chloro-1,1,2-trifluoroethyl)diethylamine.
While a tetraalkylammonium halide, azide or thiocyanate is used, the latter may be chosen, by way of example, from tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium (for example tetra-n-butylammonium), tetrapentylammonium, tetracyclohexylammonium, triethylmethylammonium, tributylmethylammonium or trimethylpropylammonium halides, azides or thiocyanates.
The procedure is carried out in an organic solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform) or in an ether (for example tetrahydrofuran) at a temperature of between xe2x88x9278 and 40xc2x0 C. (preferably of between 0 and 30xc2x0 C.). It is advantageous to carry out the procedure under argon or under nitrogen. It is understood that the use of the hydroxyl derivative of (16S) configuration leads to the derivative of (16R) configuration.
The protection and deprotection of the hydroxyl radical at the 14-position is carried out according to the usual methods which do not affect the rest of the molecule, in particular by application of the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nd ed.), A. Wiley-Interscience Publication (1991), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973). For example, the procedure is carried out by protecting with a trialkylsilyl, alkyldiphenylsilyl (for example t-butyldiphenylsilyl and t-butyldimethylsilyl) or allyl radical which are introduced and removed as described below in the examples.
Where appropriate, when it is desired to prepare a product of general formula (I) for which R3 is an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclylaliphatic ester which may be substituted, the subsequent esterification operation is carried out according to the usual methods which do not alter the rest of the molecule. More particularly, the esterification is carried out by the reaction of the acid or of a reactive derivative of the acid (for example acid chloride, reactive ester or anhydride), in the presence or otherwise of a coupling agent such as a carbodiimide (for example dicyclohexylcarbodiimide) and of a tertiary amine (trialkylamine such as triethylamine or diisopropylethylamine, or pyridine or a derivative) and optionally a catalyst such as 4-N-dimethylaminopyridine, at a temperature of between xe2x88x9240 and +80xc2x0 C., in an organic solvent such as an amide (for example dimethylformamide or N-methyl-2-pyrrolidinone), pyridine, a halogenated solvent (for example dichloromethane, dichloroethane or chloroform) or an ether (tetrahydrofuran, dioxane or dimethoxyethane). It is understood that the functions which can interfere with the reaction are protected beforehand, and then released after the reaction.
The acid or the reactive acid derivative used is prepared as described below in the examples or by analogy with the methods described.
The dihydroxylated group A streptogramin derivative of general formula (II) may be obtained by selective reduction of the natural pristinamycin component of general formula: 
in which R2 is as defined above and the bond - - - represents a single bond (stereochemistry 27R) or a double bond, followed by the separation of the 16S epimer form.
The reduction is advantageously carried out in the presence of a reducing agent such as an alkali metal borohydride, for example sodium borohydride or sodium triacetoxyborohydride, in an organic solvent chosen from chlorinated solvents (for example dichloromethane, dichloroethane, chloroform), tetrahydrofuran, acetic acid and alcohols such as methanol, ethanol or 2-propanol, at a temperature of between xe2x88x9278 and 40xc2x0 C.
The separation of the 16R epimer form and of the 16S epimer form is carried out according to the usual methods; for example, the separation of the epimer forms may be carried out by chromatography, flash chromatography, high-performance liquid chromatography (HPLC), on a chiral phase or otherwise, or centrifugal partition chromatography (CPC), from the mixture of the 16R and 16S epimers, or by crystallization.
In particular, (16S)-16-hydroxypristinamycin IIA may be prepared according to F. Le Goffic et al.; Eur. J. Med. -Chimica Therapeutica; January-February, -16(1), 69-72 (1981).
The pristinamycin derivatives of general formula (III) correspond respectively to pristinamycin IIA (PIIA), to pristinamycin IIB (PIIB), to pristinamycin IIC (PIIC), to pristinamycin IID (PIID), to pristinamycin IIF (PIIF), and to pristinamycin IIG (PIIG), which are known components of natural pristinamycin. The components PIIF and PIIG have been described in European Patent EP 614910.
Pristinamycin IIC (PIIC) and pristinamycin IID (PIID) may be obtained as described by J. C. Barrixc3xa9re et al., Expert. Opin. Invest. Drugs, 3(2), 115-31 (1994).
The preparation and separation of the components of the natural group A streptogramins [streptogramins of general formula (III)] is carried out by fermentation and isolation of the constituents from the fermentation broth according to or by analogy with the method described by J. Preud""homme et al., Bull. Soc. Chim. Fr., vol. 2, 585 (1968) or in European Patent EP 614910. Alternatively, the preparation of the natural components of group A may be carried out by specific fermentation, as described in patent application FR 2,689,518.
The streptogramin derivatives of general formula (I) may be purified, where appropriate, by physical methods such as crystallization, chromatography or CPC.
Some of the streptogramin derivatives of general formula (I) may be converted to the state of addition salts with acids, by known methods. It is understood that these salts, when they exist, are also included within the scope of the present invention.
As examples of addition salts with pharmaceutically acceptable acids, there may be mentioned the salts formed with inorganic acids (hydrochlorides, hydrobromides, sulfates, nitrates, phosphates) or with organic acids (succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, phenylsulfonates, p-toluenesulfonates, isethionates, naphthylsulfonates or camphorsulfonates, or with substitution derivatives of these compounds).
The streptogramin derivatives according to the present invention have antibacterial properties and properties synergizing the antibacterial activity of the group B streptogramin derivatives. They are particularly advantageous because of their potent activity, alone or combined.
When they are combined with a component or a derivative of the group B streptogramins, they may be chosen, depending on whether it is desired to obtain an orally or parenterally administrable form, from the natural components: pristinamycin IA, pristinamycin IB, pristinamycin IC, pristinamycin ID, pristinamycin IE, pristinamycin IF, pristinamycin IG, virginiamycin S1, S3 or S4, vernamycin B or C, etamycin or from the semisynthetic derivatives as described in patents or patent applications U.S. Pat. No. 4,618,599, U.S. Pat. No. 4,798,827, U.S. Pat. No. 5,326,782, EP 772630 or EP 770132, in particular the streptogramin derivatives of general formula: 
in which,
1. Rb, Rc, Re and Rf are hydrogen atoms, Rd is a hydrogen atom or a dimethylamino radical, and Ra is a radical of structure xe2x80x94CH2Rxe2x80x2a for which Rxe2x80x2a is 3-pyrrolidinylthio or 3- or 4-piperidylthio which may be substituted with alkyl, or alkylthio substituted with 1 or 2 hydroxysulfonyl, alkylamino, dialkylamino (itself optionally substituted with mercapto or dialkylamino), or substituted with 1 or 2 optionally substituted piperazine rings, morpholino, thiomorpholino, piperidino, 1-pyrrolidinyl, 2-, 3- or 4-piperidyl or 2- or 3-pyrrolidinyl (which may be substituted with alkyl), or alternatively Ra is a radical of structure xe2x95x90CHRxe2x80x2a for which Rxe2x80x2a is 3-pyrrolidinylamino, 3- or 4-piperidylamino, 3-pyrrolidinyloxy, 3- or 4-piperidyloxy, 3-pyrrolidinylthio, 3- or 4-piperidylthio which may be substituted with alkyl, or Rxe2x80x2a is alkylamino, alkyloxy or alkylthio substituted with 1 or 2 hydroxysulfonyl, alkylamino, dialkylamino (itself optionally substituted with dialkylamino), or with trialkylammonio, 4- or 5-imidazolyl, or with 1 or 2 optionally substituted piperazine rings, morpholino, thiomorpholino, piperidino, 1-pyrrolidinyl, 2-, 3- or 4-piperidyl or 2- or 3-pyrrolidinyl (which may be substituted with alkyl), or
xe2x80x83Ra is a 3- or 4-quinuclidinylthiomethyl radical, or alternatively
2. Ra is a hydrogen atom and
a) either Rb, Re and Rf are hydrogen atoms, Rd is a radical xe2x80x94NHCH3 or xe2x80x94N(CH3)2 and Rc is a chlorine or bromine atom, or represents an alkenyl radical containing 3 to 5 carbon atoms [if Rd is xe2x80x94N(CH3)2],
b) or Rb, Rd, Re and Rf represent a hydrogen atom and Rc is a halogen, or an aminomonoalkyl, aminodialkyl, alkyloxy, trifluoromethyloxy, thioalkyl, C1 to C3 alkyl or trihalomethyl radical,
c) or Rb, Rc, Re and Rf represent a hydrogen atom and Rd is a halogen, or an ethylamino, diethylamino or methylethylamino, alkyloxy or trifluoromethyloxy, thioalkyl, C1 to C6 alkyl, aryl or trihalomethyl radical,
d) or Rb, Re and Rf represent a hydrogen atom and Rc is halogen or an aminomonoalkyl or aminodialkyl, alkyloxy or trifluoromethyloxy, thioalkyl or C1 to C3 alkyl radical, and Rd is halogen or an amino, aminomonoalkyl or aminodialkyl, alkyloxy or trifluoromethyloxy, thioalkyl, C1 to C6 alkyl or trihalomethyl radical,
e) or Rc, Re and Rf represent a hydrogen atom and Rb and Rd represent a methyl radical;
xe2x80x83or alternatively from the semisynthetic derivatives of the group B streptogramins of general formula: 
xe2x80x83in which
Y is a nitrogen atom or a radical xe2x95x90CR3xe2x80x94,
R1 is a hydrogen atom, an alkyl radical (1 to 8 carbons), an alkenyl radical (2 to 8 carbons), a cycloalkyl radical (3 to 8 carbons), a saturated or unsaturated heterocyclyl radical (3 to 8 members), a phenyl radical, a phenyl radical which is substituted [with one or more halogen atoms or hydroxyl, alkyl, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino or dialkylamino radicals] or a radical NRxe2x80x2Rxe2x80x3, it being possible for Rxe2x80x2 and Rxe2x80x3, which are identical or different, to be hydrogen atoms or alkyl radicals (1 to 3 carbons) or to form together with the nitrogen atom to which they are attached a 3- to 8-membered heterocycle optionally containing another heteroatom chosen from oxygen, sulfur or nitrogen, optionally substituted [with an alkyl radical, an alkenyl radical (2 to 8 carbons), a cycloalkyl radical (3 to 6 carbons), a saturated or unsaturated heterocyclyl radical (4 to 6 members), a benzyl radical, a phenyl radical or a phenyl radical which is substituted as defined above for the definition of R1]
or alternatively when Y is a radical xe2x95x90CR3xe2x80x94, R1 may also be halomethyl, hydroxymethyl, alkyloxymethyl, alkylthiomethyl in which the alkyl portion is optionally substituted with NRxe2x80x2Rxe2x80x3, alkylsulfinylmethyl, alkylsulfonylmethyl, acyloxymethyl, benzoyloxymethyl, cyclopropylaminomethyl or xe2x80x94(CH2)nNRxe2x80x2Rxe2x80x3 (n being an integer from 1 to 4 and Rxe2x80x2and Rxe2x80x3 being as defined above) or alternatively if R3 is a hydrogen atom, R1 may also be formyl, carboxyl, alkyloxycarbonyl, or xe2x80x94CONRxe2x80x2Rxe2x80x3 for which Rxe2x80x2and Rxe2x80x3 are as defined above,
or alternatively when Y is a nitrogen atom, R1 may also be a radical xe2x80x94XRxc2x0 for which X is an oxygen or sulfur atom, a sulfinyl or sulfonyl radical, or an NH radical and Rxc2x0 is an alkyl radical (1 to 8 carbons), a cycloalkyl radical (3 to 6 carbons), a saturated or unsaturated heterocyclyl radical (3 to 8 members), a heterocyclylmethyl radical (3 to 8 members) in which the heterocyclyl portion is attached to the methyl radical by a carbon atom, a phenyl radical, a phenyl radical which is substituted [with one or more halogen atoms or hydroxyl, alkyl, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino or dialkylamino radicals] or a radical xe2x80x94(CH2)nNRxe2x80x2Rxe2x80x3 for which Rxe2x80x2 and Rxe2x80x3 are as defined above and n is an integer from 2 to 4, or alternatively, if X represents NH, Rxc2x0 may also represent a hydrogen atom,
R2 is a hydrogen atom or an alkyl radical (1 to 3 carbons),
R3 is a hydrogen atom or an alkyl radical, a carboxyl radical, an alkyloxycarbonyl radical, or a carbamoyl radical of structure xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3 in which Rxe2x80x2 and Rxe2x80x3 are as defined above,
Ra is a methyl or ethyl radical, and
Rb, Rc and Rd have the definitions below:
1) Rb and Rc are hydrogen atoms and Rd is a hydrogen atom or a methylamino or dimethylamino radical,
2) Rb is a hydrogen atom, Rc is a hydrogen, chlorine or bromine atom, or represents an alkenyl radical (3 to 5C), and Rd is a radical xe2x80x94NMexe2x80x94Rxe2x80x2xe2x80x3 for which Rxe2x80x2xe2x80x3 represents a radical alkyl, hydroxyalkyl (2 to 4C), or alkenyl (2 to 8C) which is optionally substituted with phenyl, cycloalkyl(3 to 6C)methyl, benzyl, benzyl which is substituted [with one or more halogen atoms or hydroxyl, alkyl, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino or dialkylamino radicals], heterocyclylmethyl or heterocyclylethyl in which the heterocyclyl portion is saturated or unsaturated and contains 5 to 6 members and one or two heteroatoms chosen from sulfur, oxygen or nitrogen optionally substituted [with an alkyl radical, an alkenyl radical (2 to 8 carbons), a cycloalkyl radical (3 to 6 carbons), a saturated or unsaturated heterocyclyl radical (4 to 6 members), a phenyl radical, a phenyl radical which is substituted as defined above for the definition of R1 or a benzyl radical], or alternatively Rxe2x80x2xe2x80x3 represents a cyanomethyl radical, or xe2x80x94CH2CORe for which either Re is xe2x80x94ORxe2x80x2e, Rxe2x80x2e being hydrogen, alkyl (1 to 6 carbons), alkenyl (2 to 6 carbons), benzyl or heterocyclylmethyl in which the heterocyclyl portion contains 5 to 6 members and 1 or 2 heteroatoms chosen from sulfur, oxygen or nitrogen or Re is an alkylamino radical, an alkylmethylamino radical, a heterocyclylamino radical or a heterocyclylmethylamino radical in which the heterocyclyl portion is saturated and contains 5 to 6 members and one or two heteroatoms chosen from sulfur, oxygen or nitrogen optionally substituted with an alkyl, benzyl or alkyloxycarbonyl radical,
3) Rb is a hydrogen atom, Rd is a radical xe2x80x94NHCH3 or xe2x80x94N(CH3)2 and Rc is a chlorine or bromine atom, or represents an alkenyl radical (3 to 5C), [if Rd is xe2x80x94N(CH3)2],
4) Rb and Rd are hydrogen atoms and Rc is a halogen atom, or an alkylamino or dialkylamino, alkyloxy, trifluoromethoxy, thioalkyl, alkyl (1 to 6C) or trihalomethyl radical,
5) Rb and Rc are hydrogen atoms and Rd is a halogen atom, or an ethylamino, diethylamino or methylethylamino, alkyloxy or trifluoromethoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl (1 to 6C), phenyl or trihalomethyl radical,
6) Rb is a hydrogen atom and Rc is a halogen atom or an alkylamino or dialkylamino, alkyloxy or trifluoromethoxy, thioalkyl or alkyl (1 to 3C) radical and Rd is a halogen atom or an amino, alkylamino or dialkylamino, alkyloxy or trifluoromethoxy, thioalkyl, alkyl (1 to 6C) or trihalomethyl radical,
7) Rc is a hydrogen atom and Rb and Rd represent a methyl radical,
as well as their salts.
It is understood that the combinations of the derivatives according to the invention and of the group B streptogramins are also included within the scope of the present invention.
The group B streptogramin derivatives of structure (B) may be prepared according to the methods described in International Application PCT/FR 99/00409.
In vitro on Staphylococcus aureus 209P, the streptogramin derivatives according to the invention have proved active at concentrations of between 0.015 and 32 xcexcg/ml alone or combined with a group B derivative such as pristinamycin IB and at concentrations of between 0.015 et 32 xcexcg/ml on Staphylococcus aureus Schiclia (resistant to meticillin) alone or combined with pristinamycin IB; in vivo, they synergise the antimicrobial activity of pristinamycin IB on experimental infections of mice with Staphylococcus aureus IP8203 at doses of between 5 and 150 mg/kg by the subcutaneous route (CD50) and the majority of them also by the oral route, at doses of between 30 and 150 mg/kg (CD50).
Finally, the products according to the invention are particularly advantageous because of their low toxicity. None of the products manifested toxicity at doses of 150 mg/kg on Staphylococcus aureus IP8203, twice per day, by the subcutaneous route or by the oral route in mice.
Of particular interest are the products of general formula (I) for which:
R1 represents a fluorine, chlorine, bromine or iodine atom or an azido or thiocyanato radical,
R2 represents a methyl radical,
R3 represents a hydrogen atom or a radical Rxe2x80x23xe2x80x94COxe2x80x94 for which Rxe2x80x23 is phenyl or phenylalkyl which are substituted or unsubstituted on the phenyl radical [with one or more radicals chosen from alkyl, optionally carrying a radical NRxe2x80x2Rxe2x80x3 in which the radicals Rxe2x80x2 and Rxe2x80x3, which are identical or different, may be hydrogen atoms or alkyl radicals which can form together with the nitrogen atom to which they are attached a 3- to 8-membered saturated or unsaturated heterocyclyl radical optionally comprising another hetero atom chosen from oxygen, sulfur or nitrogen, it being possible for the said heterocycle itself to be substituted with one or more radicals (alkyl, hydroxyalkyl, alkyloxyalkyl, alkyloxycarbonylalkyl, aryl, 3- to 8-membered saturated or unsaturated heterocyclyl or heterocyclylalkyl, or xe2x80x94CH2xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3), or alternatively Rxe2x80x2 and/or Rxe2x80x3 may be a radical hydroxyalkyl, phenyl, 3- to 8-membered saturated or unsaturated heterocyclylalkyl, xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3 for which NRxe2x80x2Rxe2x80x3 is as defined above, or alkyl or acyl which are substituted with NRxe2x80x2Rxe2x80x3 as defined above], or alternatively Rxe2x80x23 may be a phenyl radical substituted with one or more radicals [chosen from alkyl, which may be substituted with an alkyloxy or alkylthio radical themselves optionally carrying a carboxyl radical or a radical NRxe2x80x2Rxe2x80x3 as defined above, or chosen from acyloxy which may be substituted with NRxe2x80x2Rxe2x80x3 as defined above], or alternatively Rxe2x80x23 may be chosen from alkyl or cycloalkyl radicals which are optionally substituted [with a carboxyl or carboxyalkyldisulfanyl radical or with a radical NRxe2x80x2Rxe2x80x3, xe2x80x94CH2xe2x80x94NRxe2x80x2Rxe2x80x3 or xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3, or with an alkyloxycarbonyl, alkyloxy or alkyldisulfanyl radical which are optionally substituted with NRxe2x80x2Rxe2x80x3 or xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3 for which NRxe2x80x2Rxe2x80x3 is as defined above], or alternatively Rxe2x80x23 may be chosen from 3- to 8-membered saturated or unsaturated heterocycle radicals which are optionally substituted [with alkyl or acyl which are themselves optionally substituted with NRxe2x80x2Rxe2x80x3], it being understood that the heterocycles are chosen from pyrrolidinyl, imidazolyl, pyridyl, piperidinyl, piperazinyl or morpholinyl, and
the bond - - - represents a single bond (stereochemistry 27R) or a double bond, as well as their salts when they exist;
xe2x80x83and among these products, more especially:
(16R)-16-deoxo-16-fluoropristinamycin IIB;
(16R)-16-deoxo-16-thiocyanatopristinamycin IIB;
(16R)-16-deoxo-16-chloropristinamycin IIB;
(16R)-16-azido-16-deoxopristinamycin IIB;
(16R)-16-deoxo-16-fluoropristinamycin IIA.
The following examples, given with no limitation being implied, illustrate the present invention.